The current project is focused on the study of basic mechanisms of polarization of the innate immune response. Macrophages are the primary cell type responsible for the polarization of the innate immunity either by initiating and propagating inflammation (M1 phenotype) or resolving inflammation to promote tissue healing (M2 phenotype). A relative new idea is that the dysregulation of macrophage polarization with the prevalence of M1 over M2 phenotype promotes wide-spread inflammation and acute tissue injury. In the case of lungs acute lung injury (ALI) may evolve to acute respiratory distress syndrome (ARDS), a highly lethal form of respiratory failure. Hence, understanding the mechanisms by which macrophages polarize into functionally distinct phenotypes may lead to new therapeutic strategies to prevent or treat ARDS. Nuclear factor ?B (NF?B) is a master regulator of inflammation being responsible for the expression of genes that promote or resolve inflammation. While the p65/p50 configuration of NF?B promotes inflammation, the p50/p50 configuration promotes resolution. We reason that these configurations also regulate how macrophages polarize into distinct phenotypes. In this regard, we recently discovered that suppressor of cytokine signaling-1 (SOCS1) may operate the switch in NF?B function since it targets nuclear p65 but not p50 to degradation changing the relative abundances of these component subunits in the nucleus. The finding that SOCS1 is sensitive to inhibition by nitric oxide (NO) and possibly other reactive species also indicate novel molecular mechanisms by which SOCS1 activity, NF?B function, pro- and anti-inflammatory transcription, as well as macrophage polarization and inflammatory outcomes are regulated. These mechanisms are the focus of our three proposed aims: (1) to determine the mechanism by which SOCS1 promotes NF?B functional switch from that of a pro- to that of an anti-inflammatory transcriptional complex; (2) to determine if changes in the intracellular redox state of macrophages affects SOCS1 activity and NF?B function as a transcription factor and (3) Determine how SOCS1 expression in different immune cell types regulates the transition between inflammation propagation and resolution in a mouse model of bacterial pneumonia.